Background/Purpose: Circadian rhythm is a universal phenomenon that governs homeostasis of overall organism functioning as well as of individual organs. Circadian regulation of homeostatic functions in the kidneys regulates multiple renal functions including GFR, electrolyte excretion and blood pressure control. The effect of renal pathologic processes such as glomerulonephritis on circadian rhythms is not well described. In the course of genomic profiling of lupus kidneys from several mouse models of lupus nephritis we found abnormal expression of several master transcriptional regulators of circadian rhythm. Our goal was to determine how renal circadian rhythm is disrupted in lupus nephritis and the consequences of this disruption.

Methods: Perfused kidneys were obtained for molecular profiling at 4 hrly intervals over a 24hr period from groups of 5-9 young and nephritic NZB/W F1 mice. Genes with a circadian pattern of expression were identified using RAIN test. The enriched biological functions of the genes with circadian rhythm pattern at different time intervals were determined using REVIGO program. Dysregulated expression of transcriptional regulators Bmal1 and Per2 was confirmed by ELISA of renal lysates. Renal sodium and potassium excretion, urine pH and glucose, serum and urine aldosterone and blood pressure were measured at 4 hrly intervals.  The effect of remission induction on gene expression and renal function was evaluated using the same assays.

Results: We found a major effect of circadian dysregulation on renal metabolic functions in nephritic mice that was not simply due to age or altered sleep-wake cycles including a change in diurnal regulation of fatty acid metabolism, a switch in carbohydrate metabolism from gluconeogenesis to the pentose phosphate pathway, loss of diurnal variation of multiple tubular transporters, altered diurnal sodium excretion, acquisition of a high aldosterone state, increased expression of genes that mediate diurnal control of vascular constriction and reverse blood pressure dipping. This circadian dysregulation was partially reversed by remission induction therapy with correction of the abnormalities in fatty acid and carbohydrate metabolism and of abnormal blood pressure dipping phenotype but significantly less effect on the dysregulation of tubular transporters.

Conclusion: There is a profound alteration of renal circadian rhythms in mice with lupus nephritis leading to multiple adverse effects on renal homeostasis and metabolism as well as blood pressure dipper status that are only appreciated upon multiple sampling of kidneys at sequential intervals. Our study indicates the role of inflammation in causing renal circadian disruption and suggests a potential role for circadian agonists in the treatment of lupus nephritis.   

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/reversible-dysregulation-of-renal-circadian-rhythm-in-lupus-nephritis/